Forms of pravastatin sodium

ABSTRACT

New polymorphic forms of pravastatin sodium are provided. Each of the new forms is selectively obtained by crystallization from different solvent systems, each solvent system having a protic component, and by controlling the rate of crystallization through temperature. The new polymorphic forms are suitable for use as active substances of pharmaceutical dosage forms for reduction of serum cholesterol levels in the bloodstream.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.09/736,796, filed Dec. 14, 2000, which issued as U.S. Pat. No. 7,001,919on Feb. 21, 2006, which claims the benefit under 35 U.S.C. § 1.119(e) ofU.S. Provisional Patent Application No. 60/170,685, filed Dec. 14, 1999and U.S. Provisional Patent Application No. 60/190,649, filed Mar. 20,2000, the contents of all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to statins, and more particularly to novelpolymorphic forms of pravastatin sodium.

BACKGROUND OF THE INVENTION

Pravastatin is a member of the class of pharmaceutical compounds calledstatins. Statins currently are the most effective treatment for loweringserum cholesterol levels in patients with atherosclerosis andhypercholesteremia. Pravastatin is the common medicinal name of thechemical compound[1S-[1α(β*,δ*)2α,6α,8β(R*),8aα]]-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoicacid. (CAS Registry No. 81093-37-0) The molecular structure ofpravastatin is represented by Formula (I). “Pravastatin sodium” isdefined as the monosodium salt of pravastatin, whether hydrated oranhydrous, solvated or unsolvated.

According to U.S. Pat. No. 4,346,227, incorporated herein by reference,pravastatin is reported as having been first isolated as a metabolite ofcompactin by M. Tanaka et al. during a study of compactin metabolism.The '227 patent discloses the isolation of pravastatin in its lactoneform, as the methyl ester of the free carboxylic acid and as themonosodium salt of the free carboxylic acid (“pravastatin sodium”).Pravastatin sodium was analyzed by nuclear magnetic resonancespectroscopy, infrared (“IR”) spectroscopy, ultraviolet spectroscopy andthin layer chromatography. Pravastatin sodium was analyzed in solid formby IR spectroscopy using the conventional technique of co-mixing withpotassium bromide (“KBr”) and then compressing to form a KBr window orpellet. The IR spectrum of the pravastatin sodium obtained by absorptionbands at 3400, 2900, 1725, 1580 cm⁻¹. All other spectral measurementsare repeated on pravastatin sodium in solution.

The present invention relates to new crystal forms of pravastatin sodiumand compositions containing them. Polymorphism is the property of somemolecules and molecular complexes to assume more than one crystallineform in the solid state. A single molecule may give rise to a variety ofcrystal forms (also called “polymorphs”) having distinct physicalproperties. The existence of more than one crystal form can bedetermined in a laboratory by comparison of the angles at which X-rayradiation reflected from the forms undergoes constructive interferenceand by comparing the absorptions of incident infrared radiation atdifferent wavelengths. The former technique is known as X-raydiffraction spectroscopy and the angles at which constructiveinterference occurs are known as reflections.

The differences in the physical properties of polymorphs result from theorientation and intermolecular interactions of adjacent molecules(complexes) in the bulk solid. Accordingly, polymorphs are distinctsolids sharing the same molecular formula yet having distinctadvantageous and/or disadvantageous physical properties compared toother forms in the polymorph family.

One of the most important physical properties of a polymorphicpharmaceutical compound is the solubility of each of its forms inaqueous solution, particularly the solubility in gastric juices of apatient. Other important properties relate to the ease of processing theform into pharmaceutical dosages, such as the tendency of a powdered orgranulated form to flow and the surface properties that determinewhether crystals of the form will adhere to each other when compactedinto a tablet.

SUMMARY OF THE INVENTION

The present invention is directed to new polymorphic forms ofpravastatin sodium. These forms are designated Form A, Form B, Form C,Form D, Form E, Form F, Form G, Form H, Form H1, Form I, Form J, Form Kand Form L. The invention is also directed to methods of making each ofthe pravastatin sodium polymorphs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form A.

FIG. 2 is a characteristic infrared absorption spectrum of pravastatinsodium Form A.

FIG. 3 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form B.

FIG. 4 is a characteristic infrared absorption spectrum of pravastatinsodium Form B.

FIG. 5 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form C.

FIG. 6 is a characteristic infrared absorption spectrum of pravastatinsodium Form C.

FIG. 7 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form D.

FIG. 8 is a characteristic infrared absorption spectrum of pravastatinsodium Form D.

FIG. 9 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form E.

FIG. 10 is a characteristic infrared absorption spectrum of pravastatinsodium Form E.

FIG. 11 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form F.

FIG. 12 is a characteristic infrared absorption spectrum of pravastatinsodium Form F.

FIG. 13 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form G.

FIG. 14 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form H.

FIG. 15 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form H1.

FIG. 16 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form I.

FIG. 17 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form J.

FIG. 18 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form K.

FIG. 19 is a characteristic powder X-ray diffraction pattern ofpravastatin sodium Form L.

DETAILED DESCRIPTION OF THE INVENTION

We have discovered new polymorphic forms of pravastatin sodium that canbe distinguished from the known amorphous pravastatin sodium and fromeach other by their powder X-ray reflections and their infraredabsorption spectra.

All powder X-ray diffraction patterns were obtained by methods known inthe art using a Philips X-ray powder diffractometer, with goniometermodel 1050/70, at scanning speed of 2° min.⁻¹. Copper radiation ofλ=1.5418 Å was used.

The infrared spectrum was obtained in a Nujol mull using a Perkin ElmerParagon 1000 FT-IR spectrometer at 4 cm⁻¹ resolution with 16 scans. Thecharacteristic infrared absorption bands of the novel forms ofpravastatin sodium will not necessarily be observed in the IR spectrumof a sample that has been dissolved, as for example in chloroform orcarbon tetrachloride, for IR analysis. That is: some IR bands may becharacteristic of pravastatin in the solid state; others arecharacteristic of pravastatin sodium whether in the solid or solutionphase.

Pravastatin crystal forms show DSC curves with multiple endothermic andexothermic events due to water desorption and phase transitions. Themelting peak observed in all forms except form B is in the range ofabout 174-176° C. Form B has a melting point at about 187° C.

Pravastatin crystal forms exhibit hygroscopic behavior. The water uptakeat 80% relative humidity after 1 week was up to about 15%. Afterexposure at 100% relative humidity, all the forms of pravastatin sodiumtransform to Form C with about 30% relative humidity. It was also foundthat all the crystal forms, except Form B, were transformed to Form D byheating at 120° C. for 2 hours.

Characteristics of Pravastatin Sodium Polymorphs

Pravastatin sodium Form A is characterized by reflections in the powderX-ray diffraction pattern at 3.9, 4.5, 6.2, 7.2, 8.6, 9.2, 10.0, 11.6,12.0, 17.0 and 20.0±0.2 degrees, detected at reflection angle 2θ. Thediffraction pattern is reproduced in FIG. 1. Of these, the reflectionsat 3.9, 4.5, 6.2, and 7.2±0.2 degrees are especially characteristic.Form A may also be distinguished by its infrared absorption spectrumwhich is shown in FIG. 2 obtained in a Nujol mull. Form A hascharacteristic; absorption bands at 686, 826, 842, 864, 917, 939, 965,1013, 1040, 1092, 1111, 1156, 1184, 1265, 1310, 1330, 1576 and 1726,±2cm⁻¹.

Pravastatin sodium Form B is distinguished by reflections in the powderX-ray diffraction pattern that are observed at 3.6, 6.1, 6.6, 9.0, 9.6,10.1, 16.4, 16.8 and 18.6±0.2 degrees detected at the reflection angle2θ. The diffraction pattern is reproduced in FIG. 3. The reflections at3.6, 6.1, 6.6, 9.0, 9.6, 10.1 and 18.6±0.2 degrees are the most intenseand in that sense the most characteristic, the reflections at 3.6, 6.1and 6.6±0.2 degrees being the most intense of all. Form B may further bedistinguished by its IR spectrum, provided as FIG. 4, obtained from aNujol mull. Absorption bands are observed at 614, 692, 739, 824, 842,854, 868, 901, 914, 936, 965, 1011, 1028, 1039, 1072, 1091, 1111, 1129,1149, 1161, 1185, 1232, 1245, 1318, 1563, 1606, 1711 and 1730±2 cm⁻¹.

Pravastatin sodium Form C may be distinguished by reflections in thepowder X-ray diffraction pattern that are observed at about 4.8, 7.6,8.6, 10.0, 11.8, 12.4, 13.0, 15.5, 16.0, 17.4, 17.9, 18.4, 19.7, 21.0,21.8 and 22.8±0.2 degrees, detected at reflection angle 2θ. Thereflections observed at 4.8, 7.6, 8.7, 10.0, 13.0, 16.0, 17.4 and19.7±0.2 degrees are characteristic and, of these, the reflections at4.8, 10.0, 13.0, 16.0 and 17.4±0.2 degrees are especiallycharacteristic. The diffraction pattern is reproduced in FIG. 5. Form Cmay further be distinguished by its IR spectrum, provided as FIG. 6,obtained from a Nujol mull. Absorption bands of pravastatin sodium FormC are observed at 742, 829, 851, 870, 926, 940, 964, 1013, 1038, 1078,1090, 1146, 1166, 1174, 1194, 1257, 1268, 1313, 1328, 1567 and 1728±2cm⁻¹.

Pravastatin sodium Form D may be distinguished from the other forms ofcrystalline and amorphous pravastatin sodium by reflections in thepowder X-ray diffraction pattern that are observed at 3.6, 6.3, 9.8 and17.1±0.2 degrees, detected at reflection angle 2θ. The diffractionpattern is reproduced in FIG. 7. Form D may further be distinguished byits IR spectrum, provided as FIG. 8, obtained from a KBr window usingthe same equipment and methodology as was used to obtain the IR spectrumof Form A. Characteristic absorption bands of pravastatin sodium Form Dare observed at 824, 843, 854, 914, 939, 965, 1013, 1041, 1079, 1091,1157, 1186, 1266, 1566, 1606 and 1728±2 cm⁻¹.

Pravastatin sodium Form E exhibits reflections in the powder X-raydiffraction pattern at about 4.6, 9.2, 10.3, 11.2, 12.1, 16.6, 18.3 and20.6±0.2 degrees, detected at a reflection angle of 2θ. Form E isreadily distinguished from the other forms of crystalline and amorphouspravastatin sodium by the reflections at 4.6, 9.2, 10.3, 12.1, 16.6,18.3 and 20.6±0.2 degrees, the reflections at 10.3, 12.1 and 16.6degrees being especially characteristic of Form E. The diffractionpattern is reproduced in FIG. 9. Form E may further be distinguished byits IR spectrum, provided as FIG. 10, obtained from a Nujol mull.Characteristic absorption bands of pravastatin sodium Form E areobserved at 781, 829, 853, 939, 964, 1016, 1043, 1078, 1158, 1179, 1266,1300, 1329, 1401, 1573 and 1727±2 cm⁻¹.

Pravastatin sodium Form F may be distinguished from the other forms ofpravastatin sodium by the reflection in the powder X-ray diffractionpattern that occurs at about 4.6±0.2 degrees, detected at reflectionangle 2θ. The absence of other diffraction peaks points to the amorphousnature of this form. The diffraction pattern is reproduced in FIG. 11.Form F may be distinguished by its IR spectrum, provided as FIG. 12,obtained from a KBr window. Absorption bands are observed at 781, 829,853, 939, 964, 1016, 1043, 1079, 1157, 1181, 1265, 1300, 1330, 1400,1576 and 1727±2cm⁻¹.

Pravastatin sodium Form G may be distinguished by reflections in thepowder X-ray diffraction pattern that are observed at about 4.5, 9.2,10.0, 12.2, 16.0, 16.5, 17.6, 18.6, 19.5, 20.5, and 22.8±0.2 degrees,detected at reflection angle 2θ. The diffraction pattern is reproducedin FIG. 13. Pravastatin sodium Form G has a DSC scan characterized bytwo endotherms at about 165° and 173° C. followed by decomposition.

Pravastatin sodium Form H may be distinguished by reflections in thepowder X-ray diffraction pattern that are observed at about 3.5, 5.9,9.0, 10.1, 11.7, 12.1, 14.7, 17.0 19.0, 19.9, 20.6, 21.8 and 22.9±0.2degrees, detected at reflection angle 2θ. Of these, the peaks at 3.5,5.9, 9.0, 10.1 and 17.0±0.2 degrees are particularly diagnostic. Thediffraction pattern is reproduced in FIG. 14.

Pravastatin sodium Form H1 may be distinguished from the other forms ofcrystalline and amorphous pravastatin sodium by reflections in thepowder X-ray diffraction pattern that are observed at about 3.5, 5.9,6.8, 8.9, 10.1, 11.7, 12.3, 13.3, 14.8, 17.6, 18.8, 20.0, 20.8, and22.9±0.2 degrees, detected at reflection angle 2θ. Of these, the peaksat 3.5, 5.9, 8.9, 10.1, 17.6, 18.8 and 20.8±0.2 degrees are particularlydiagnostic. The diffraction pattern is reproduced in FIG. 15.

Pravastatin sodium Form I may be distinguished from the other forms ofcrystalline and amorphous pravastatin sodium by reflections in thepowder X-ray diffraction pattern that are observed at about 4.4, 5.2,5.8, 6.5, 7.5, 8.3, 9.0, 9.8, 10.2, 11.2, 13.2, 14.0, 16.5, 17.5, 18.3,18.7, 19.5, 20.5, 21.5 and 23.0±0.2 degrees, detected at reflectionangle 2θ. Of these, the peaks at 4.4, 5.2, 5.8, 6.5, 9.0, 13.2, and14.0±0.2 degrees are particularly diagnostic. The diffraction pattern isreproduced in FIG. 16.

Pravastatin sodium Form J may be distinguished from the other forms ofcrystalline and amorphous pravastatin sodium by reflections in thepowder X-ray diffraction pattern that are observed at about 3.3, 3.8,6.0, 6.8, 7.5, 8.8, 9.3, 10.2, 11.2, 11.7, 13.5, 13.9, 14.5, 15.6, 16.3,17.7, 18.1, 18.7, 19.5, 20.0, 20.4, 21.7, 22.3, 24.2, and 26.1±0.2degrees, detected at reflection angle 2θ. Of these, the peaks at 3.8,6.0, and 16.3±0.2 degrees are particularly diagnostic. The diffractionpattern is reproduced in FIG. 17.

Pravastatin sodium Form K may be distinguished by reflections in thepowder X-ray diffraction pattern that are observed as a broad peakbetween 15 and 25 as well as peaks at 4.1, 6.8 and 10.2 degrees measuredat reflection angle 2θ. The diffraction pattern is reproduced in FIG.18.

Pravastatin sodium Form L may be distinguished from the other forms ofcrystalline and amorphous pravastatin sodium by reflections in thepowder X-ray diffraction pattern that are observed at about 4.5, 5.0,9.0, 10.1, 12.3, 13.4, 15.0, 16.6, 17.6, 18.5 19.5, 20.2, 21.2 and22.7±0.2 degrees, detected at reflection angle 2θ. Of these, the peaksat 16.6, 17.6, and 18.5±0.2 degrees are particularly diagnostic. Thediffraction pattern is reproduced in FIG. 19.

Procedures for Crystallizing Polymorphs of Pravastatin Sodium

It will be appreciated by those skilled in the art of crystallizationthat attainment of a particular crystalline form of a compound is highlydependent upon exacting control of conditions. These conditions include,among other parameters, the composition of the solvent system employed,the pH of the solvent system, the temperature profile and the form ofany crystals that are added to induce crystallization from asupersaturated solution.

Pravastatin sodium Forms A though F may each be obtained byrecrystallization from two-component solvent systems having a proticcomponent and an aprotic component. The term “protic” refers to thepresence of a labile proton like a hydroxyl proton or carboxylic acidproton. Water is a protic solvent. “Aprotic” means the absence of labileprotons. The term “solvents” is used conventionally to mean chemicalcompounds into which a solute, such as pravastatin sodium, is dissolvedor dispersed.

The pravastatin sodium polymorphs A-F, obtained by recrystallization,are highly dependent upon the solvent system from which the form iscrystallized. Pravastatin sodium tends to crystallize as Forms A, B andE from solvent systems having a protic component that is either ethanolor an ethanol:water mixture. In contrast, pravastatin sodium tends tocrystallize as forms C, D and F from solvent systems that have a proticcomponent that is water alone. We have been able to obtain each of thedifferent forms described above by crystallizing pravastatin sodium froma solvent mixture consisting of a protic solvent and an aprotic solvent.The aprotic solvent is selected from ethyl acetate, acetonitrile,acetone and acetonitrile:acetone mixtures.

Temperature is another important parameter for, among other reasons, itseffect on the economics of producing a particular form. It is highlydesirable to be able to conduct a crystallization of pravastatin sodiumat temperatures of −10° C. or above. −10° C. is approximately the lowerlimit of temperatures that are obtainable by cooling with cold brine. Toobtain lower temperatures, a specialized cooling apparatus, orequivalently, a cooled material like dry ice or liquid nitrogen that hasbeen made cold with a special cooling apparatus must be used.Consequently, the attainment of lower temperatures increases the cost ofproduction. The increased cost may, in fact, be enough to discourage theuse of pharmaceuticals in certain crystalline forms with an attendantsacrifice in solubility properties and other desirable properties of thecrystalline forms. Accordingly, we have developed procedures forcrystallizing pravastatin sodium in each of the forms of the presentinvention that may be conducted at a crystallization temperature ofabout −10° C. or above. The choice to use a lower temperature is withinthe province of one skilled in the art informed by this disclosure.

In order to obtain each of the pravastatin sodium Forms A through F inhigh yield with only moderate cooling, solvent systems that aremoderately to highly concentrated (i.e. typically greater than 0.05 M)in pravastatin sodium have been developed. According to these preferredsolvent systems, the pravastatin sodium is preferably first dissolved inthe protic component of the solvent system. Then, the protic componentis preferably diluted with the aprotic component in order to decreasethe solubility of the pravastatin sodium. The concentration of thepravastatin sodium in the protic component before dilution is notcritical. However, after dilution, the concentration of pravastatinsodium is preferably in the range of 0.05 to 0.5 M. Dilution may beconducted either before, during or after cooling the solution to thecrystallization temperature.

The aprotic solvent may be a nonpolar solvent, such as hexane, petroleumether, carbon tetrachloride and the like. The aprotic solvent may alsobe a polar aprotic solvent. In particular, acetonitrile, acetone, ethylacetate and acetonitrile:acetone mixtures comprise a spectrum of aproticcomponents from which each of the novel pravastatin sodium forms may beobtained. Aprotic solvents are preferably used from 4 to 20 fold excesson a volume-to-volume basis over the protic component.

The use of ethanol alone as the protic component of the solvent systemfavors the crystallization of pravastatin sodium Form B, provided thesolvent system has been adjusted to a pH of about 8.2 to about 8.7,preferably about 8.5. Equal-volume mixtures of ethanol and water, on theother hand, tend to favor crystallization of Form A. Comparison ofExamples 1 and 2 with Example 3 demonstrates this solvent effect withspecific illustrative embodiments.

While, generally speaking, the form of pravastatin sodium obtained byrecrystallization is not especially sensitive to the choice of aproticsolvent among these exemplary aprotic solvents, it will be noted thatthe use of ethyl acetate in a 20:1 excess over a 1:4 H₂O:ethanol proticcomponent promotes crystallization of pravastatin sodium in Form E (SeeExample 8). This result is to be compared to crystallization fromethanol and ethanol:water mixtures in Forms A and B which is promoted byan acetonitrile aprotic component (See Examples 1-3). In addition, whenthe acetonitrile is used in an amount that is around the lower range ofthe proportion of aprotic component in the solvent system, i.e. about 4to about 7 fold excess over the protic component, pravastatin sodiumForm B is favored. On the other hand, when acetonitrile is used in anintermediate amount, i.e. about 13 to about 17 fold excess, Form A isfavored.

As noted above, a solvent system having a protic component of wateralone favors the section crystallization of pravastatin sodium as FormsC, D or amorphous Form F. Formation of amorphous Form F is promoted byadjustment of the pH of the solvent system from about pH 8.7 to about pH10.3, preferably about pH 9 to about pH 10. The pH may be adjusted bycontacting with a weak cationic exchange resin such as Amberlite® IRC-50(See Examples 9 and 10). If the pH is not adjusted, Form F typically isnot obtained in pure form. Forms C and D may be obtained from a solventsystem wherein water is the only protic component and wherein the pH ofthe solution is not adjusted for the purpose of obtaining Form F.

None of the aforementioned parameters operates independently. So, in theexamples concluding this description and preceding the claims, whichdisclose the best mode for obtaining each of the forms, it will be seenthat variations in several parameters at once combine to produce anoptimal yield and purity of the desired form. In particular, the choiceof solvent system, concentration and temperature profile are notindependent. The use of acetonitrile, acetone and acetonitrile:acetonemixtures as the aprotic component, rather than ethyl acetate, allows fora greater concentration of pravastatin sodium in solution at ambienttemperature without premature crystallization. Thus, without heating ofthe solution of pravastatin sodium in the protic component prior todilution, the solution may be diluted with acetone and/or acetonitrileto a range of 0.1 to 0.2 M without premature crystallization (See, e.g.Examples 7, 9-11). When ethyl acetate is used as the aprotic component,the solution of pravastatin sodium in the protic component is preferablyheated to about 40° C. or above, more preferably about 60° C. beforeaddition of the ethyl acetate. Preferably, with heating, ethyl acetateis added to dilute the solution to less than 0.1 M.

The rate of cooling from ambient or elevated temperature, whichever thecase may be, should not be excessively rapid in order to realize maximumselectivity of the other conditions that have been chosen in order toobtain the desired form. Rapid cooling, typically, will tend to reduceselectivity and result in mixtures of two or more forms rather than anindividual pure form. Accordingly, manipulation of the recrystallizationparameters to obtain mixtures of the novel forms of pravastatin havingdesirable characteristics is considered to be within the scope of theinvention. Typically, in order to obtain any one of the forms in highpurity the rate of cooling may be about from 2° C. h⁻¹ to 35° C. h⁻¹,but the rate of cooling is preferably between about 2° C. h⁻¹ to 5.8° C.h⁻¹.

Once crystallization is complete, the crystals are then isolated byfiltration, decantation of the solvent, removal of the solvent or othersuch method, preferably filtration. The crystals optionally may then bewashed and dried according to methods known to the art.

Pravastatin sodium Form G may be prepared by storing pravastatin sodiumForm F for 2 weeks at a relative humidity of about 40 to about 80%.

Pravastatin sodium Forms A, H, H1, I, J, K may each be obtained byconversion from Form D or F. The conversion process consists of treatingpravastatin sodium Form D or F with an alcohol. In one embodiment thealcohol treatment consists of exposing the first polymorph to the vaporsof a solvent for a time period. The period of time may be overnight ormay last for three weeks. In an alternative embodiment the solventtreatment comprises suspended Form D or F in a solvent for a period oftime.

The treatment is performed at room temperature. The temperature may bebetween about 15° C. and 35° C. Optimally, the temperature is about 25°C.

The polymorphic form of pravastatin sodium obtained is dependent on thetreatment solvent. For example, treating Form D or F with ethanol vaporsproduces Form A. Treating form D or F with methanol vapors produces FormH. The relationship between the treatment solvent and the polymorphicform of pravastatin sodium produced is summarized in Table I, andillustrated in Example 15, 16, 17, 18, 19, and 20.

TABLE I Starting Resulting Incubation Polymorph Polymorph Solvent TimeExposure D or F A Ethanol 3 weeks Vapors D or F H Methanol 3 weeksVapors D or F H1 Methanol Overnight Suspension D or F I Isopropyl 3weeks Vapors Alcohol D or F J Butanol 3 weeks Vapors D or F K Ethanol,Overnight Suspension Isopropyl Alcohol and Butanol

Most of these forms have a jelly appearance. By drying these samples at60° C., vacuum overnight, the powdered Form D is obtained.

Treatment of Hypercholesteremia with Pravastatin Sodium Polymorphs

More pravastatin sodium Forms A, B, C, D, E, F, G, H, H1, I, J, K and Lare useful for hypercholesteremia therapy and for this purpose they areadministered to a mammalian patient in a dosage form. Dosage forms maybe adapted for administration to the patient by oral, buccal,parenteral, ophthalmic, rectal and transdermal routes. Oral dosage formsinclude tablets, pills, capsules, troches, sachets, suspensions,powders, lozenges, elixirs and the like. The pravastatin sodium formsalso may be administered as suppositories, ophthalmic ointments andsuspensions, and parenteral suspensions, which are administered by otherroutes. The most preferred route of administration of the pravastatinsodium forms of the present invention is oral.

While the description is not intended to be limiting, the invention doesnot pertain to true solutions of any of the novel pravastatin sodiumforms in which the properties of the solid forms of pravastatin sodiumare lost. However, the use of the novel forms to prepare such solutions(e.g. so as to deliver, in addition to pravastatin sodium, a solvate tosaid solution in a certain ratio with a solvate) is considered to bewithin the contemplated invention.

The dosage forms may contain one or more of the novel forms ofpravastatin sodium or, alternatively, may contain one or more of thenovel forms of pravastatin sodium in a composition. Whether administeredin pure form or in a composition, the pravastatin sodium form(s) may bein the form of a powder, granules, aggregates or any other solid form.The compositions of the present invention include compositions fortableting. Tableting compositions may have few or many componentsdepending upon the tableting method used, the release rate desired andother factors. For example, compositions of the present invention maycontain diluents such as cellulose-derived materials like powderedcellulose, microcrystalline cellulose, microfine cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose saltsand other substituted and unsubstituted celluloses; starch;pregelatinized starch; inorganic diluents like calcium carbonate andcalcium diphosphate and other diluents known to the pharmaceuticalindustry. Yet other suitable diluents include waxes, sugars and sugaralcohols like mannitol and sorbitol, acrylate polymers and copolymers,as well as pectin, dextrin and gelatin.

Further excipients that are within the contemplation of the presentinvention include binders, such as acacia gum, pregelatinized starch,sodium alginate, glucose and other binders used in wet and drygranulation and direct compression tableting processes. Excipients thatmay also be present in a solid composition of the novel forms ofpravastatin sodium further include disintegrants like sodium starchglycolate, crospovidone, low-substituted hydroxypropyl cellulose andothers. Additional excipients include tableting lubricants likemagnesium and calcium stearate and sodium stearyl fumarate; flavorings;sweeteners; preservatives; pharmaceutically acceptable dyes and glidantssuch as silicon dioxide.

Capsule dosages, of course, will contain the solid composition within acapsule which may be made of gelatin or other encapsulating material.Tablets and powders may be coated. Tablets and powders may be coatedwith an enteric coating. The enteric-coated powder forms may havecoatings comprising phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, they may be employed with suitableplasticizers and/or extending agents. A coated tablet may have a coatingon the surface of the tablet or may be a tablet comprising a powder orgranules with an enteric-coating.

In human subjects with normal hepatic function and moderate body weight,a reduction in serum cholesterol levels is typically observed with dailydosages of 10 mg or more of pravastatin sodium. A daily oral regimen isthe most commonly prescribed method of administration. Preferred oraldosages of the present invention contain from about 10 mg to about 40 mgof pravastatin sodium Forms A, B, C, D, E, F, G, H, H1, I, J, K, and Lor their mixtures.

Having thus described the present invention with reference to certainpreferred embodiments, the following examples are provided to furtherillustrate methods by which novel Forms A, B, C, D, E, F, G, H, H1, I,J, K, and L of pravastatin sodium may be obtained. One skilled in theart will recognize variations and substitutions in the methods asdescribed and exemplified which do not depart from the spirit and scopeof the invention.

EXAMPLES

“Ethanol” refers to absolute ethanol. Acetonitrile, acetone and ethylacetate were regular grade.

Example 1 Preparation of Pravastatin Sodium Form A

Pravastatin sodium (5 g) was dissolved in a 1:1 mixture of ethanol:water(5 ml). The pH was raised to 8.5 by addition of 2M sodium hydroxide inwater (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90ml) was added to the mixture and then the mixture was stirred atelevated temperature for one hour. The mixture was allowed to cool to20-25° C. (“ambient temperature”), was held at ambient temperature fortwo hours and then cooled to 5° C. and maintained at 5° C. for 12 hours,whereupon pravastatin sodium crystallized. The crystals were thenisolated by filtration and washed with acetonitrile (2×10 ml) and driedunder vacuum at 50° C. X-ray diffraction analysis revealed the presenceof Form A. Pravastatin Form A was obtained in 92% yield.

Example 2 Preparation of Pravastatin Statin Form A

Pravastatin sodium (5 g.) was dissolved in a 2.85:1 mixture ofethanol:water (10.8 ml). The pH was raised to 8.5 by addition of 2Msodium hydroxide in water (1.2 ml). Acetonitrile (200 ml) was thenslowly added to the mixture at ambient temperature over a two hourperiod. The mixture was stirred at ambient temperature for another twohours and then cooled to 5° C. and maintained at 5° C. for 12 hours,whereupon pravastatin sodium crystallized. The crystals were thenisolated by filtration and washed with acetonitrile (2×10 ml) and driedunder vacuum at 50° C. X-ray diffraction analysis revealed the presenceof Form A. Pravastatin sodium Form A was obtained in 96% yield.

Example 3 Preparation of Pravastatin Sodium Form B

Pravastatin sodium (5 g) was dissolved in ethanol (35.5 ml). The pH wasraised to 8.5 by addition of 2M sodium hydroxide in water (1.5 ml). Thebasic solution was heated to 60° C. and then diluted with acetonitrile(213 ml). The solution was maintained at elevated temperature for onehour and then was allowed to cool to ambient temperature and wasmaintained at ambient temperature for two hours. The solution was thencooled to 5° C. and maintained at that temperature for 12 hours,whereupon pravastatin sodium crystallized. The crystals were isolated byfiltration and rinsed, first with ethyl acetate (2×45 ml) and secondwith n-hexane (2×45 ml). The rinse solvents had been precooled to 5° C.After rinsing, the crystals were dried under vacuum at 50° C. X-raydiffraction analysis revealed the presence of Form B. Pravastatin sodiumForm B was obtained in 87% yield.

Example 4 Preparation of Pravastatin Sodium Form C

Pravastatin sodium (10 g) was dissolved in deionized water (26 ml) anddiluted with a 2:3 mixture of acetonitrile:acetone (130 ml). Theresulting solution was then warmed to 40° C. and maintained at thattemperature for one half hour while acetonitrile (160 ml) was slowlyadded. The solution was then cooled to 5° C. While cooling, pravastatinsodium began to crystallize at 19.5° C. The mixture was maintained at 5°C. for five hours, after which time the crystals were isolated byfiltration, washed with acetone that had been pre-cooled to 5° C., anddried under vacuum at 50° C. X-ray diffraction analysis revealed thepresence of Form C. Pravastatin sodium Form C was obtained in 76% yield.

Example 5 Preparation of Pravatatin Sodium Form D

Pravastatin sodium (600 g) was dissolved in 0.73 M sodium hydroxide inwater (600 ml). The resulting solution was diluted with acetonitrile(1.2 L) and then decolorized by stirring over charcoal (30 g) for 30min. The charcoal was removed by filtration and rinsed with 2:1acetone:water (1.8 L). The pravastatin sodium solution and rinsate werecombined and diluted with acetonitrile (17 L). The dilute solution wasmaintained at ambient temperature (20-25° C.) for one hour and thencooled to 5° C. and stirred at that temperature for 4 hours, whereuponpravastatin sodium crystallized. The crystals were filtered and slurriedwith ethyl acetate (6 L) at 5° C. to remove residual acetonitrile. Thecrystals were then washed with ethyl acetate that had been pre-cooled to−5° C. and dried under vacuum at 50° C. X-ray diffraction analysisrevealed the presence of Form D. Pravastatin sodium Form D was obtainedin 97% yield.

Example 6 Preparation of Pravastatin Sodium Form D

Pravastatin sodium (7 g) was dissolved in deionized water (13 ml) anddiluted with acetone (14.3 ml). The resulting solution was stirred overcharcoal (0.07 g.) to decolorize. The charcoal was removed by filtrationand rinsed with a 10:1 mixture of acetone:water (15.7 ml). The combinedpravastatin sodium solution and rinsate was then diluted with acetone(42.8 ml) and cooled to −10° C. At the reduced temperature, more acetone(143 ml) was slowly added over one half hour. The solution was thenmaintained at −10° C. for three hours during which time pravastatinsodium crystallized. The crystals were then isolated by filtration,washed with 1% water in acetone that had been pre-cooled to −10° C. (28ml) and then again with anhydrous acetone (28 ml). The crystals werethen dried under vacuum at 50° C. X-ray diffraction analysis revealedthe presence of Form D. The conversion of amorphous pravastatin sodiumto pravastatin sodium Form D occurred in 85% yield. Before drying thecrystals were Form L, after drying the crystals were Form D.

Example 7 Preparation of Pravastatin Sodium Form D

Pravastatin sodium (25 g) was dissolved in deionized water (65 ml) anddiluted with 1:1.44 acetonitrile:acetone (330 ml). The resultingsolution was cooled to 5° C. While cooling, pravastatin sodium startedto crystallize at 9° C. After crystallization appeared to cease, acetonethat had been precooled to 5° C. (650 ml) was added to the mixture andthe mixture was maintained at 5° C. for another three hours. Thecrystals were isolated by filtration and washed with 1:3:22water:acetone:acetonitrile that had been pre-cooled to 5° C. (25 ml).The crystals were then slurried with ethyl acetate that had beenpre-cooled to 5° C. (50 ml) and dried under vacuum at 50° C. X-raydiffraction analysis revealed the presence of Form D. Pravastatin sodiumForm D was obtained in 70% yield.

Example 8 Preparation of Pravastatin Sodium Form E

Pravastatin sodium (5 g) was dissolved in 4:1 ethanol:water (12.5 ml)and warmed to 60° C. The solution was then diluted with ethyl acetate(250 ml) and the dilute solution was maintained at elevated temperaturefor one hour. The solution was then allowed to cool to ambienttemperature and was maintained at that temperature for two hours. Thesolution was then cooled to 5° C. and maintained at reduced temperaturefor three hours, whereupon pravastatin sodium crystallized. The crystalswere isolated by filtration, rinsed with ethyl acetate (2×30 ml) anddried under vacuum at 50° C. X-ray diffraction analysis showed thepresence of Form E. Pravastatin sodium Form E was obtained 87% yield.

Example 9 Preparation of Pravastatin Sodium Form F

Pravastatin sodium (10 g) was dissolved in water (24.5 ml) and dilutedwith acetonitrile (26 ml). The resulting solution was stirred overcharcoal (0.1 g.) to decolorize. Amberlite® IRC-50 cationic ion exchangeresin (H⁺ form) was added to the stirred mixture to raise the pH to9.09. The charcoal and ion exchange resin were removed by filtration andrinsed with a 10:1 mixture of acetonitrile:water (16.5 ml). The combinedpravastatin sodium solution and rinsate was diluted with 2.1:1acetone:acetonitrile (115 ml), cooled to 5° C. and maintained at reducedtemperature for two hours. pravastatin sodium crystallized. Aftercrystallization appeared to cease, acetonitrile (260 ml) that had beenpre-cooled to 5° C. was added and the mixture was maintained at reducedtemperature for another three hours. The crystals were isolated byfiltration and washed with 1:3:22 water:acetone:acetonitrile (40 ml)that had been pre-cooled to 5° C. The crystals were then slurried withprecooled ethyl acetate (100 ml) and dried under vacuum at 50° C. X-raydiffraction analysis showed the presence of Form F. Pravastatin sodiumForm F was obtained in 74% yield.

Example 10 Preparation of Pravastatin Sodium Form F

Pravastatin sodium (10 g) was dissolved in deionized water (24.5 ml) anddiluted with acetonitrile (26 ml). The resulting solution was stirredover charcoal (0.1 g.) to decolorize. Then, the pH was raised to 9.01 byaddition of Amberlite® IRC-50 cationic exchange resin (H⁺ form). Thecharcoal was removed by filtration and rinsed with a 10:1 mixture ofacetonitrile:water (16.5 ml). The combined pravastatin sodium solutionand rinsate was then diluted with 2.1:1 acetone:acetonitrile (115 ml)and cooled to 5° C. The solution was maintained at reduced temperaturefor three hours, during which time pravastatin sodium crystallized. Thecrystals were isolated by filtration and washed with 1:3:22water:acetone:acetonitrile that had been pre-cooled to 5° C. (40 ml).The crystals were slurried with ethyl acetate that had been pre-cooledto 5° C. and then dried under vacuum at 50° C. X-ray diffractionanalysis showed the presence of Form F. Pravastatin sodium Form F wasobtained in 90% yield.

Example 11 Preparation of Pravastatin Sodium Form F

Pravastatin sodium (5 g) was dissolved in deionized water (13 ml) anddiluted with acetone (65 ml). The resulting solution was cooled to 5° C.While cooling, pravastatin sodium Form F began to crystallize at 9° C.The mixture was maintained at 5° C. for five hours. Then, acetone thathad been pre-cooled to 5° C. was added to the mixture and the mixturewas kept at 5° C. for another three hours, after which timecrystallization was judged to be complete. The crystals were thenisolated by filtration, washed with acetone that had been pre-cooled to5° C. (10 ml) and dried under vacuum at 50° C. Pravastatin sodium Form Fwas obtained in 87% yield.

Example 12 Preparation of Mixture of Pravastatin Sodium Forms D and F

Pravastatin sodium (10 g.) was dissolved in deionized water (24.5 ml)and diluted with acetonitrile (26 ml). The resulting solution wasstirred over charcoal (0.1 g.) to decolorize. The charcoal was removedby filtration and rinsed with a 10:1 mixture of acetonitrile:water (16.5ml). The combined pravastatin sodium solution and rinsate was dilutedwith acetonitrile (11 ml) and warmed to 40° C. At the elevatedtemperature, acetone (60 ml) was slowly added over one half hour. Thesolution was then cooled to a temperature of 10° C. over three hours.After the solution had attained a temperature of 12° C., the mixture wasseeded with a crystal of pravastatin sodium Form D. At 11.3° C., thesolution was diluted with acetone (200 ml). After the three hours hadpassed, the mixture of solution and crystals was cooled to 5° C. andmaintained at that temperature for three hours. The crystals were thenremoved by filtration, washed with acetone that had been pre-cooled to5° C. (40 ml) and dried under vacuum at 50° C. The crystals were foundby X-ray diffraction to be a mixture of pravastatin sodium Form D andForm F. The mixture of pravastatin sodium Forms D and F was obtained in77% yield.

Example 13 Preparation of Mixture of Pravastatin Sodium Forms C and D

Pravastatin sodium (10 g) was dissolved in deionized water (18 ml) anddiluted with acetone (20 ml). The resulting solution was stirred overcharcoal (0.1 g) to decolorize. The charcoal was removed by filtrationand rinsed with a 10:1 mixture of acetonitrile:water (20 ml). Thecombined pravastatin sodium solution and rinsate was then diluted withacetone (60 ml) and warmed to 40° C. The solution was maintained atelevated temperature for half an hour while acetone (190 ml) was slowlyadded. The solution was cooled to 10° C. While being cooled, thesolution was seeded with a crystal of pravastatin sodium Form D at 13°C. The solution was then maintained at 10° C. for three hours. Thenacetone (190 ml) was added and the solution was cooled to 5° C. Another190 ml of acetone was added and the mixture was stirred at 5° C. forthree hours, during which time crystallization was complete. Thecrystals were isolated by filtration, washed with acetone that had beenpre-cooled to 5° C., and dried under vacuum at 50° C. The crystals wereidentified by X-ray diffraction as a mixture of pravastatin sodium FormsC and D. The mixture of pravastatin sodium Forms C and D was obtained in89% yield.

Example 14 Preparation of Pravastatin Sodium Form F

Pravastatin sodium (10 g) was dissolved in deionized water (20 ml). ThepH of the aqueous solution was adjusted to 7.1 by addition of Amberlite®IRC-50 cationic ion exchange resin (H⁺ form). The solution was thendiluted with acetone (120 ml) and then heated to 40° C. Another 130 mlof acetone was slowly added to the mixture over a period of 30 min. Thesolution was then cooled to 5° C. over 3 hours. When the mixture reacheda temperature of 25° C., it was seeded with crystals of Form F. Themixture was maintained at 5° C. for 20 h, over which time pravastatinsodium crystallized from the mixture. The crystals were isolated byfiltration and washed with acetone (40 ml). The crystals were then driedunder vacuum at 60° C. X-ray diffraction analysis showed the presence ofForm F. Pravastatin sodium Form F was obtained in 84% yield.

Example 15 Preparation of Pravastatin Sodium Form G

Pravastatin Form G is obtained when pravastatin Form F is stored for twoweeks at relative humidity of between 40-80%. The resulting solid wasanalyzed by X-ray diffraction without further treatment.

Example 16 Preparation of Pravastatin Sodium Form H

Pravastatin sodium Form H was prepared by treating Form D or F withethanol vapors for three weeks at room temperature. The procedure was asfollows. A 100-200 g sample of pravastatin sodium Form D or F was keptin a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing ethanol. The larger bottle was sealed in orderto create a saturated atmosphere. The resulting solid was analyzed byX-Ray diffraction without further treatment. Form H could also beconverted to Form D by drying under vacuum overnight.

Example 17 Preparation of Pravastatin Sodium Form H1

Pravastatin sodium Form Hi was prepared by suspending about 0.5 to 1.4 gof Form D in about 0.6 ml methanol overnight at room temperature, in asealed 1.10 ml bottle with a sealed cap and a magnetic stirrer Theresulting solid was analyzed by X-ray diffraction analysis withoutfurther treatment.

Example 18 Preparation of Pravastatin Sodium Form I

Pravastatin sodium Form I was prepared by treating Form D or F withisopropyl vapors for three weeks at room temperature. The procedure wasas follows. A 100-200 g sample of pravastatin sodium Form D or F waskept in a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing few ml of isopropyl alcohol. The larger bottlewas sealed in order to create a saturated atmosphere. The resultingsolid was analyzed by X-Ray diffraction analysis without furthertreatment. Form I could also be transformed to Form D by drying undervacuum overnight.

Example 19 Preparation of Pravastatin Sodium Form J

Pravastatin sodium Form J was prepared by treating Form D or F withbutanol vapors for three weeks at room temperature. The procedure was asfollows. A 100-200 g sample of pravastatin sodium Form D or F was keptin a 10 ml open glass bottle. The open bottle was introduced into alarger bottle containing few ml of butanol. The larger bottle was sealedin order to create a saturated atmosphere. The resulting solid wasanalyzed by X-Ray diffraction analysis without further treatment. Form Jcould also be transformed to Form D by drying under vacuum overnight.

Example 20 Preparation of Pravastatin Sodium Form K

Pravastatin sodium Form K was obtained by suspending 0.8 g pravastatinin about 2 ml ethanol and stirring overnight at RT. The resulting solidwas analyzed by X-Ray diffraction analysis without further treatment.

Example 21 Preparation of Pravastatin Sodium Form D

Pravastatin sodium (about 100 mg) of any polymorph beside Forms B or Dwas kept in an oven at 120° C. for 2 hours. The powder was then analyzedby X-ray diffraction and found to be Form D.

Example 22 Preparation of Pravastatin Sodium Form C

Pravastatin sodium was exposed at 100% relative humidity for one week.The power was then analyzed by X-ray diffraction without furthertreatment and was found to be Form C.

Example 23 Preparation of Pravastatin Sodium Form L and Form D

A solution was prepared, containing 80 kg pravastatin sodium and 144 kgwater. The pH of the solution was set to 7.2, by IRC-50 weakly acidiccation exchange resin. Acetone (320 L) was added to the solution and itwas treated with 0.8 kg charcol to decolorize. The charcoal was filteredwith a solution of acetone:water, 10:1 (176 L). The solution was warmedto 40° C. Acetone (176 L) was added to the solution. The mixture iscooled at a rate of 2° C./h⁻¹ rate. The solution is seeded at 32° C. by0.1% (0.08 kg) pravastatin sodium (Form D). The mixture was cooled to 2°C. and stirred for 2-4 hour.

Pravastatin crystals were filtered and washed with 160 L acetonecontaining 2% water and cooled to between 2-5° C. Then the wet cake waswashed once more with 160 L of pure acetone. The product was dried undervacuum by gradual heating to 60° C. The crystals were identified byX-ray diffraction as Form L. The water content was 16.8% and the acetonecontent was 0%. After prolonged drying the water content was reduced to10.7%. A mixture of Form L and D was identified. Further drying reducedthe water content to 2.5% water content and the pravastatin sodium wastransformed to pure Form D.

1. A pharmaceutical composition comprising a crystalline pravastatinsodium or hydrate thereof comprising an X-ray powder diffraction patterncomprising characteristic peaks at 3.6, 6.1, 6.6, 9.0, 9.6, 10.1, 16.4,16.8, and 18.6±0.2 degrees measured at reflection angle 2θ and apharmaceutically acceptable carrier, wherein the pharmaceuticalcomposition has a coating.
 2. A pharmaceutical composition of claim 1,wherein the coating comprises at least one material selected from thegroup consisting of phthalic acid cellulose acetate, hydroxypropylmethylcellulose phthalate, a polyvinyl alcohol phthalic,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid, methyl methacrylate and mixtures thereof.3. A pharmaceutical composition of claim 1, wherein the coating is anenteric coating.
 4. A pharmaceutical composition of claim 1, wherein thepharmaceutical composition is selected from a dosage form selected fromthe group consisting of granules, aggregates, a tablet, a capsule, apowder, or combination.
 5. A pharmaceutical composition of claim 4,wherein the pharmaceutical composition is an oral dosage form andcontains from about 10 mg to about 40 mg of pravastatin sodium.